The focus of this competing continuation proposal is the localization and characterization of susceptibility genes for Tourette's Disorder (TD) and related conditions. The investigators are members of a longstanding international collaboration, the Tourette Syndrome Association International Consortium on Genetics (TSAICG). Previous studies completed by members of this group suggest that the mode of transmission of TD and related disorders is consistent with the existence of genes that have a significant impact on the manifestation of TD. During the current award we conducted a genomewide linkage analysis of our samples of affected sibpair and multigenerational families. The results pointed strongly to a TD locus on Chromosome 2p [-log(p) = 4.00] and also provided evidence for several additional TD localizations, with -log(p) scores ranging from 2.0 to 3.5. We are proposing three genetic mapping studies using high-throughput SNP genotyping: Project 1 will follow up our linkage findings with fine-mapping genotyping, focusing particularly on 2p; Project 2 will search for additional TD loci through a whole genome association study on 800 trios ascertained from isolated populations; Project 3 will follow up the results of Projects 1 and 2, with a very dense set of SNPs to be genotyped in a sample (n=7200) with substantial power to detect association. The results of Project 3 will lead to genetic investigation of a small number of positional candidate genes. Functional studies of the most promising candidate genes identified through the above studies will be undertaken. Phenotypic data for new subjects sampled during the first two years of this proposal will be obtained by direct semi-structured interview of affected children and both parents. Additional analyses are proposed to define more accurately the inherited components of the TD phenotype.